Fosaprepitant dimeglumine

Description

Fosaprepitant for injection is a sterile, lyophilized formulation containing fosaprepitant dimeglumine, which is a prodrug of aprepitant, functioning as a substance P/neurokinin-1 (NK1) receptor antagonist and an antiemetic agent. Fosaprepitant is chemically described as 1‑Deoxy-1-(methylamino)-D-glucito[3-[[[2R,3S)-2-[(1R)-1-3,5-bis(trifluoromethyl)phenylethoxy]-3-(4‑fluorophenyl)-4-morpholinyl]methyl]-2,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]phosphonate(2:1) (salt). The molecular formula of fosaprepitant is C23H22F7N4O6P•2(C7H17NO5), and it has a molecular weight of 1004.83 g/mol. Fosaprepitant dimeglumine appears as a white to off-white powder and is freely soluble in water, soluble in N,N-Dimethylsulfoxide, and insoluble in n-hexane. Each vial of fosaprepitant for injection contains 245.3 mg of fosaprepitant dimeglumine, which is equivalent to 150 mg of fosaprepitant free acid. Inactive ingredients include edetate disodium (5.4 mg), lactose anhydrous (375 mg), polysorbate 80 (75 mg), sodium hydroxide, and/or hydrochloric acid (for pH adjustment).

Uses and Indications

Fosaprepitant for injection is indicated for the prevention of acute and delayed nausea and vomiting in adults and pediatric patients aged 6 months and older, when used in combination with other antiemetic agents. This drug is specifically indicated for the prevention of nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC), including high-dose cisplatin, as well as for the prevention of delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC).

Limitations of use include that fosaprepitant for injection has not been studied for the treatment of established nausea and vomiting. There are no teratogenic or nonteratogenic effects reported for this medication.

Dosage and Administration

Fosaprepitant for injection is administered intravenously. For adult patients, the recommended dosage is 150 mg on Day 1, infused over a period of 20 to 30 minutes. It is essential to complete the infusion approximately 30 minutes prior to the initiation of chemotherapy.

For pediatric patients aged 6 months to 17 years, weighing at least 6 kg, dosing regimens vary by age and should be referenced in the Full Prescribing Information. For single-dose chemotherapy regimens, a single dose of fosaprepitant for injection is administered on Day 1. In cases of single or multi-day chemotherapy regimens, a 3-day fosaprepitant for injection regimen is recommended on Days 1, 2, and 3. Alternatively, aprepitant capsules or fosaprepitant for oral suspension may be utilized on Days 2 and 3.

When administering fosaprepitant for injection to pediatric patients, it should be delivered through a central venous catheter. The infusion should last 30 minutes for patients aged 12 years to 17 years, and 60 minutes for those aged 6 months to less than 12 years. As with adult patients, the infusion must be completed approximately 30 minutes prior to chemotherapy.

Contraindications

Use of this drug is contraindicated in patients with a known hypersensitivity to any component of the formulation. Additionally, concurrent use with pimozide is contraindicated due to potential drug interactions that may exacerbate adverse effects.

Warnings and Precautions

Hypersensitivity reactions, including anaphylaxis and anaphylactic shock, may occur during or shortly after the infusion of fosaprepitant. In the event of such symptoms, it is imperative to discontinue the drug immediately. Reinitiation of fosaprepitant is contraindicated in patients who have experienced hypersensitivity reactions with prior use.

Infusion site reactions, such as thrombophlebitis, necrosis, and vasculitis, have been predominantly reported in patients receiving vesicant chemotherapy. To minimize the risk of these reactions, it is advised to avoid infusing fosaprepitant into small veins. Should a severe reaction develop, the infusion must be discontinued, and appropriate treatment should be administered.

Fosaprepitant may interact with warfarin, a substrate of CYP2C9, leading to a potential decrease in the International Normalized Ratio (INR) of prothrombin time. It is essential to monitor INR levels during the two-week period following the initiation of fosaprepitant, with particular attention to measurements taken between 7 to 10 days post-initiation.

The efficacy of hormonal contraceptives may be diminished during treatment with fosaprepitant and for 28 days following its administration. Healthcare professionals should advise patients to utilize effective alternative or backup methods of contraception during this period.

Fosaprepitant is a weak inhibitor of CYP3A4, while its active metabolite, aprepitant, acts as a substrate, inhibitor, and inducer of CYP3A4. Clinicians should refer to the Full Prescribing Information for detailed recommendations regarding contraindications, potential adverse reactions, and necessary dosage adjustments for fosaprepitant and any concomitant medications.

In the case of hypersensitivity symptoms, it is crucial to discontinue the drug and seek emergency medical assistance. If hypersensitivity reactions occur, patients should be instructed to stop taking fosaprepitant and contact their healthcare provider immediately.

Regular monitoring of INR is recommended during the specified timeframe to ensure patient safety and effective management of anticoagulation therapy.

Side Effects

Most common adverse reactions reported in adults (≥2%) include fatigue, diarrhea, neutropenia, asthenia, anemia, peripheral neuropathy, leukopenia, dyspepsia, urinary tract infection, and pain in extremity.

Hypersensitivity reactions, which may include anaphylaxis and anaphylactic shock, can occur during or shortly after infusion. In the event of such symptoms, it is imperative to discontinue the drug and not to reinitiate fosaprepitant if similar symptoms have occurred with previous use.

Infusion site reactions, such as thrombophlebitis, necrosis, and vasculitis, have been predominantly reported in patients receiving vesicant chemotherapy. To minimize the risk of these reactions, it is advised to avoid infusion into small veins. Should a severe reaction develop, the infusion should be discontinued, and appropriate treatment should be administered.

Additional adverse reactions may occur in patients with known hypersensitivity to any component of this drug or those concurrently using pimozide. It is noteworthy that adverse reactions observed in pediatric populations are similar to those seen in adults.

Drug Interactions

There are currently no documented drug interactions associated with this medication. Additionally, there are no known interactions with laboratory tests. As such, no specific recommendations for dosage adjustments or monitoring are necessary at this time.

Packaging & NDC

The table below lists all NDC Code configurations of Fosaprepitant, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

The safety and effectiveness of fosaprepitant have been established in pediatric patients aged 6 months to 17 years for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC). This use is supported by evidence from adequate and well-controlled studies in adults, along with additional safety, efficacy, and pharmacokinetic data specific to pediatric patients within this age range.

Efficacy and safety findings are further corroborated by an adequate and well-controlled study of a 3-day oral aprepitant regimen in pediatric patients aged 6 months to 17 years. The safety of the 3-day fosaprepitant for injection regimen in this population was also supported by an open-label study involving 100 patients receiving HEC or MEC.

It is important to note that the safety and effectiveness of fosaprepitant dimeglumine for the prevention of nausea and vomiting associated with HEC or MEC have not been established in patients younger than 6 months of age.

Geriatric Use

Elderly patients, defined as those aged 65 and over, comprised 27% of the 1649 adult cancer patients treated with intravenous fosaprepitant in high emetic risk (HEC) and moderate emetic risk (MEC) clinical studies, with 5% of patients aged 75 and over. Clinical experience with fosaprepitant has not identified significant differences in therapeutic responses between elderly and younger patients.

However, caution is advised when dosing geriatric patients due to the increased likelihood of diminished hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies. It is essential for healthcare providers to monitor these patients closely and consider potential dose adjustments based on individual health status and functional capacity.

Pregnancy

There are insufficient data on the use of fosaprepitant in pregnant patients to inform a drug-associated risk. Animal reproduction studies have shown that no adverse developmental effects were observed in rats or rabbits exposed during the period of organogenesis to systemic drug levels (AUC) approximately equivalent to the exposure at the recommended human dose (RHD) of 150 mg.

In embryofetal development studies, aprepitant was administered to pregnant rats at oral doses up to 1,000 mg/kg twice daily and to pregnant rabbits at the maximum tolerated dose of 25 mg/kg/day. No embryofetal lethality or malformations were observed at any dose level in either species. The exposures (AUC) in pregnant rats and rabbits at these doses were approximately equivalent to the exposure at the RHD of 150 mg. It is noted that aprepitant crosses the placenta in both rats and rabbits.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Given the lack of data in human pregnancies, healthcare professionals should weigh the potential benefits against the risks when considering the use of fosaprepitant in pregnant patients.

Lactation

There are insufficient data on the use of fosaprepitant in lactating mothers to inform a drug-associated risk. Aprepitant has been shown to cross the placenta in animal studies conducted in rats and rabbits. However, data regarding the excretion of aprepitant in human breast milk and its effects on breastfed infants are not available. Therefore, caution is advised when administering this medication to lactating mothers.

Renal Impairment

There is no specific information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in this patient population.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

In cases of overdosage with fosaprepitant or aprepitant, there is currently no specific information available regarding targeted treatment protocols. In the event of an overdose, it is recommended that fosaprepitant be discontinued immediately. Healthcare professionals should provide general supportive treatment and closely monitor the patient for any adverse effects.

Due to the antiemetic properties of fosaprepitant, it is important to note that drug-induced emesis may not be effective in managing fosaprepitant overdosage. Therefore, alternative supportive measures should be considered.

Additionally, it is crucial to understand that aprepitant is not removed from the body through hemodialysis, which may influence the management approach in cases of overdose. Continuous assessment and supportive care remain the cornerstone of managing patients who have experienced an overdose of these agents.

Nonclinical Toxicology

Oral administration of aprepitant did not adversely affect the fertility or general reproductive performance of male or female rats at doses up to the maximum feasible dose of 1,000 mg/kg twice daily. The exposure levels in male rats were lower than those at the recommended adult human dose of 150 mg, while the exposure in female rats was approximately equivalent to the adult human exposure.

Carcinogenicity studies were conducted in Sprague-Dawley rats and CD-1 mice over a duration of 2 years. In the rat studies, animals received oral doses ranging from 0.05 to 1,000 mg/kg twice daily. The highest dose resulted in systemic exposures to aprepitant that were approximately equivalent to (in female rats) or less than (in male rats) the adult human exposure at the recommended human dose of 150 mg. Treatment with aprepitant at doses of 5 to 1,000 mg/kg twice daily led to an increased incidence of thyroid follicular cell adenomas and carcinomas in male rats. In female rats, the treatment resulted in hepatocellular adenomas at doses of 5 to 1,000 mg/kg twice daily, as well as hepatocellular carcinomas and thyroid follicular cell adenomas at doses of 125 to 1,000 mg/kg twice daily.

In the mouse carcinogenicity studies, animals were treated with oral doses ranging from 2.5 to 2,000 mg/kg/day. The highest dose produced systemic exposure approximately twice that of the adult human exposure at the recommended human dose of 150 mg. Treatment with aprepitant resulted in the development of skin fibrosarcomas at doses of 125 and 500 mg/kg/day in male mice. It is noteworthy that carcinogenicity studies were not conducted with fosaprepitant.

Aprepitant and fosaprepitant were not found to be genotoxic in several assays, including the Ames test, the human lymphoblastoid cell (TK6) mutagenesis test, the rat hepatocyte DNA strand break test, the Chinese hamster ovary (CHO) cell chromosome aberration test, and the mouse micronucleus test. Fosaprepitant, when administered intravenously, is rapidly converted to aprepitant. In fertility studies involving fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were observed following oral administration of aprepitant.

Postmarketing Experience

Hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been reported in patients receiving fosaprepitant. Severe skin reactions, which may manifest as rash, skin peeling, or sores, have also been observed. Infusion site reactions (ISR) at or near the infusion site have occurred with fosaprepitant for injection, particularly in conjunction with certain chemotherapy agents known to cause skin damage, such as vesicants. These severe ISRs may present with symptoms including pain, swelling, and redness, and in some cases, necrosis of skin tissue has been reported.

Most ISRs can occur following the first, second, or third dose of treatment, with some lasting up to two weeks or longer. In adults, the most frequently reported side effects associated with fosaprepitant for injection include fatigue, weakness or numbness in the extremities, diarrhea, dyspepsia, low white blood cell and red blood cell counts, urinary tract infections, and pain in the arms and legs. In pediatric patients aged 6 months to 17 years, common side effects include low red blood cell count, low platelet count, low white blood cell count, and low white blood cell count accompanied by fever.

Patients are advised to consult their healthcare provider for medical advice regarding side effects and may report adverse events to the FDA at 1-800-FDA-1088.

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling (Patient Information) to understand the medication fully. It is important to inform patients that hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been reported in individuals taking fosaprepitant. Patients should seek immediate medical attention if they experience any signs or symptoms of a hypersensitivity reaction, such as hives, rash and itching, skin peeling or sores, flushing, difficulty in breathing or swallowing, dizziness, rapid or weak heartbeat, or feelings of faintness.

Healthcare providers should also instruct patients to seek medical attention if they notice new or worsening signs or symptoms of an infusion site reaction. These may include erythema, edema, pain, necrosis, vasculitis, or thrombophlebitis at or near the infusion site.

Patients must be encouraged to discuss all medications they are currently taking, including other prescription medications, non-prescription medications, and herbal products, to ensure safe and effective use of fosaprepitant.

For patients on chronic warfarin therapy, it is essential to follow the healthcare provider's instructions regarding blood draws to monitor their INR during the two-week period, particularly at 7 to 10 days following the initiation of fosaprepitant with each chemotherapy cycle.

Additionally, patients should be informed that the administration of fosaprepitant may reduce the efficacy of hormonal contraceptives. Therefore, it is crucial to instruct patients to use effective alternative or back-up methods of contraception, such as condoms and spermicides, during treatment with fosaprepitant and for one month following its administration.

Storage and Handling

Fosaprepitant for injection is supplied in vials that must be stored under refrigeration. It is essential to maintain a temperature range of 2°C to 8°C (36°F to 46°F) to ensure the integrity of the product.

Once reconstituted, the final drug solution remains stable for 24 hours at ambient room temperature, which is defined as at or below 25°C (77°F). Any unused portion of the reconstituted solution should be discarded to ensure patient safety and product efficacy.

Additional Clinical Information

Clinicians should monitor the International Normalized Ratio (INR) in patients on chronic warfarin therapy during the two weeks following the initiation of fosaprepitant, particularly around days 7 to 10 of each chemotherapy cycle. It is important to avoid infusing fosaprepitant for injection into small veins or through a butterfly catheter to minimize complications.

Patients should be counseled to use effective alternative or back-up methods of contraception during treatment with fosaprepitant and for one month after administration. Postmarketing experience has indicated that serious hypersensitivity reactions, including anaphylaxis and anaphylactic shock, may occur during or shortly after the infusion of fosaprepitant. Additionally, infusion site reactions (ISRs) have been reported, with severe cases requiring medical or surgical intervention.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Fosaprepitant as submitted by BluePoint Laboratories. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)